虽然转移是导致癌症相关死亡的主要原因之一，但将实体肿瘤细胞的依附依赖性重新编程为循环肿瘤细胞（CTCs）的专门机制在转移时仍然是一个关键的挑战领域。我们分析了血细胞特异性转录本并选择了能够以可诱导和可逆转的方式将依附细胞的依附依赖性重新编程为悬浮细胞的关键的附着-悬浮转换（AST）因子。通过一系列的体外和体内试验，评估了AST的机制。从乳腺癌和黑色素瘤小鼠异种移植模型和原发性肿瘤、CTCs和转移性肿瘤的配对样本中收集的样本，分析了单细胞RNA测序（scRNA-seq）和组织染色来验证AST因子在CTCs中的作用。通过shRNA敲低、基因编辑和药物抑制来进行功能丧失实验，以阻断转移并延长生存期。我们发现一种被称为AST的生物学现象，通过定义的造血转录调节因子将依附细胞重新编程为悬浮细胞，固态肿瘤细胞通过接管，进而传播成为CTCs。在侵袭过程中，我们揭示AST因子在原发性肿瘤和CTCs来自病人的德诺沃转移和小鼠模型中的关键作用。通过硝酸噻唑衍生物对AST因子进行药理阻断，在乳腺癌和黑色素瘤细胞中消除了CTC形成并抑制了肺转移，而不影响原发性肿瘤的生长。我们证明，悬浮细胞可以直接由附着细胞通过添加附着细胞不能“票据录入”的转录因子获得转移特征。此外，我们的发现将盛行的癌症治疗范例扩展到直接干预癌症的转移扩散。©2023年作者。

Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge.We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival.We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell-matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth.We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.© 2023. The Author(s).